The development, activation, and specificity of T lymphocytes were investigated. Structure/function analysis of T cell receptor expression showed that regions of both AlphaBeta and GammaDelta antigen receptors corresponding to the complimentarity determining regions of the variable chains influence specificity and thus must play an important role in interaction with antigen/MHC ligands. Molecular analysis of endogenous murine superantigens was performed, with the goal of analyzing their expression in distinct cell type and their interaction with T cell receptors. Bacterial enterotoxin superantigens were shown to induce VBeta-specific tolerance in peripheral T cells, both by clonal anergy and clonal deletion. A general role for TCR/self antigen interactions in T cell development was suggested by the direct demonstration of a requirement for positive selection in the functional maturation of thymocytes expressing the GammaDelta receptor heterodimer. T cells expressing a class I MHC-specific GammaDelta transgenic receptor did not proliferate to receptor-mediated signals and did not exit from the thymus to populate peripheral lymphoid organs when they developed in a Beta2 microglobulin (e.g. class I MHC) deficient environment. This indicates that receptor-mediated signalling is a required step in the differentiation of this T cell subset.